Heart failure (HF) is the leading cause of adult hospitalization in the industrialized world and imposes a substantial burden on the public health. Over the past two decades, a large body of research using transgenic models has implicated a growing number of transcription factors and microRNAs as mediators of myocardial hypertrophy and dysfunction. Because few of these mediators have been confirmed in human hearts, there has been minimal progress in applying these insights to human HF therapeutics. We propose to overcome these barriers by leveraging unique bioresources at three U.S. transplant centers that have amassed repositories of high-quality myocardium from more than 1,900 human subjects over the past 15 years. The overall goals of this proposal are to use integrative genomics to test whether transcriptional regulatory programs identified in animal models are relevant in human HF and to perform unbiased screens for regulators of myocardial gene expression in human subjects. Integrative genomics elucidates disease mechanism by combining phenotype data with whole-genome genotypes and gene expression in a tissue of interest. To apply these approaches to the human heart, we have assembled a multidisciplinary team of experts in heart failure, clinical investigation, cardiac biology, and the genetics of complex disorders. In Aim 1, we will perform a case-control study (n=1000) using integrated SNP and expression data to test which of 40 pre-specified transcriptional regulators contribute to advanced HF in humans. In Aim 2, we will perform a cross-sectional study (n=1000) using integrated SNP and expression data across a broad range of myocardial phenotypes to test whether the same candidate regulators contribute to pathological remodeling. In both aims, secondary analyses and network modeling will enable genome-wide screens for unanticipiated mechanisms of transcriptional regulation in the human heart. In Aim 3, we will test whether our most promising results identify genetic risk factors for cardiac remodeling in the general population through collaboration with EchoGen, a genome-wide association meta-analysis of echocardiographic traits in seven community-based cohorts (N=18,000). This research will test the relevance of knowledge derived from years of animal research while employing an unbiased discovery approach to reveal unanticipated mechanisms of human myocardial disease. Doing so will accelerate the translation of scientific knowledge to HF therapeutics. Moreover, all data and biosamples will be made available to the scientific community to promote a broad and durable impact on HF research.